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WO2017146994A1 - Agglomération contrôlée de médicament ou mélanges médicament-excipient micronisés - Google Patents

Agglomération contrôlée de médicament ou mélanges médicament-excipient micronisés Download PDF

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Publication number
WO2017146994A1
WO2017146994A1 PCT/US2017/018246 US2017018246W WO2017146994A1 WO 2017146994 A1 WO2017146994 A1 WO 2017146994A1 US 2017018246 W US2017018246 W US 2017018246W WO 2017146994 A1 WO2017146994 A1 WO 2017146994A1
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WO
WIPO (PCT)
Prior art keywords
chamber
powder
particulate material
agglomerates
agglomerate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2017/018246
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English (en)
Inventor
Atul KARANDE
Sai Prasanth Chamarthy
Chinedu OREKIE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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Publication of WO2017146994A1 publication Critical patent/WO2017146994A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/12—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic in rotating drums
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes

Definitions

  • the present invention relates to a process for preparing powder agglomerates from a rotating apparatus.
  • the powder agglomerates formed by the process of the present invention are useful for preparing common pharmaceutical dosage forms, especially dried powder dosage forms for dry powder inhalation.
  • Micron-sized drug and/or excipient particles are widely used in the pharmaceutical industry in a multitude of applications.
  • Common dosage forms which contain such particles include oral dosage forms, e.g., tablets and capsules, topical dosage forms, e.g., creams, injectable dosage forms, e.g., suspensions, and inhalation dosage forms, e.g., dry powder dosage forms and metered dose inhaler forms.
  • micronization increases the effective surface area of the active pharmaceutical ingredient (API) and results in a better dissolution rate and bioavailability. Due to increased bioavailability of the API, the dosage form requires a smaller amount of API, which in turn results in a more cost-effective product, and a lower exposure of the patient to the API.
  • API active pharmaceutical ingredient
  • drug particles administered in dry powder inhalers, metered dose inhalers, and nebulizers require drug particles to be in the micron size range to allow their passage into the deeper respiratory tract and thus, achieve the desired pharmacological effect.
  • Comminuting drug and/or substances into small particles, and then processing the particles into the desired dosage forms poses several challenges.
  • inter-particulate forces exceed the gravitational forces exerted on these particles, which causes the powders to flow poorly in drug product processing steps.
  • This phenomenon hinders the physical handling, storage and downstream processing through unit operations such as passage through hoppers, compression into tablets, filling of capsules or sachets, and metering into dry-powder inhalers.
  • Poor flow characteristics of micron-sized particles impede the accurate metering of drug-containing formulation into the dosage form or device, e.g., an inhalation device.
  • Agglomeration of powders enlarges the size of the materials to be processed and improves the flow properties of the complexed, micronized particles.
  • Common agglomeration methods often involve use of tertiary processes, such as addition of binders (e.g., during wet granulation) or introduction of mechanical forces, e.g., roller compaction, that cause the primary particles to bind to each other even more strongly.
  • binders e.g., during wet granulation
  • mechanical forces e.g., roller compaction
  • an optimized agglomeration process results in particles which are strong enough to have adequate flow, storage, handling, and metering characteristics, yet are weak enough to readily disperse into primary particles upon interaction with physiological fluid (e.g., disintegration for oral solid dosage forms upon contact with gastrointestinal fluids), or upon actuation of an inhaler.
  • physiological fluid e.g., disintegration for oral solid dosage forms upon contact with gastrointestinal fluids
  • these processes include agitating a powder bed in a horizontal, parallel plane resulting in a circular or elliptical flow pattern of the powder bed.
  • Interactive energy distributes into the powder bed contained in a vessel by vibrations and/or shear.
  • These processes suffer from inhomogeneous distribution of the interactive energy thoughout the powder bed which results in agglomerates having variable powder properties.
  • the effective operating parameters that provide agglomerates of suitable properties often restrict the quantities of agglomerates that can be prepared since scale-up of such processes only exacerbates the variability in the resulting powder agglomerates' properties.
  • Prior art devices for preparing agglomerates frequently utilize spheronizers driven primarily by competing radial and inertial forces in the horizontal plane which coagulate particles into agglomerates and round them off by particle-particle and particle-wall interactions.
  • certain devices depicted in FIG. 1 A have a spinning horizontal disc (1) with a vertical rotational axis (2) onto which a wet or dry mass of material is metered for agglomeration and/or spheronization.
  • the metered mass spins with a spiral pathway and immediately fans out from the center of the disc only to be contained by the vertical wall (3) of the spheronizer. Inter- particle collisions and particle-wall interactions cause the particles to then coagulate, densify, and round off over time.
  • FIG. IB Another prior art device commonly used for preparing agglomerates is depicted in FIG. IB.
  • the device has a disc (1) which orbits in the horizontal plane, traveling in elliptical orbit (4) about a vertical rotational axis (2), causing the metered mass to travel in swirls (eddies) between the center of the disc and the wall of the spheronizer (3).
  • inter-particle collisions and particle-wall interactions cause the particles to then coagulate, densify, and round off over time.
  • radial forces attenuate with increasing distance from the center of rotation. This phenomenon effectively limits the size and capacity of any such spheronizer device and, hence, batch scaling is a last resort for increasing capacity.
  • U.S. Patent No. 4,161,516 to John H. Bell discloses, inter alia, a medicament in pellet form characterized in that the pellet form is soft, and comprises an agglomeration of individual medicament particles have a diameter of less than 10 microns.
  • the patent discloses that the soft pellets can be prepared by controlled agglomeration of particles of medicament which are either intrinsically or have been rendered, self-agglomerative to a controlled agglomeration.
  • the present invention provides a process for preparing powder agglomerates from a rotating apparatus comprising:
  • the present invention provides a process which is highly scaleable since it allows preparation of both small and large quantities of powder agglomerates with minimal process development.
  • the inventive process also provides powder agglomerates of consistent quality which have have excellent flow characteristics.
  • the process results in powder agglomerates which have sufficient strength to withstand packaging and storage and yet, retain sufficient softness to disperse into primary particles on mixing with physiological fluids or upon discharge from an inhaler or nebulizer.
  • FIG. 1 A is a depiction of a prior art spheronizing apparatus in which a chamber charged with the granular material spins in the horizontal plane about a vertical rotational axix.
  • FIG. IB is a depiction of a prior art spheronizing apparatus in which a chamber charged with the granular material spins with an elliptical orbit in the horizontal plane about a vertical rotational axis.
  • FIG. 2 depicts an apparatus (10) useful for conducting the process of the present invention.
  • FIG. 3 is an enlarged and cutaway view of the apparatus depicted in FIG. 2.
  • FIG. 4 is a cut-way view depicting an enclosed chamber used in one embodiment of the process of the present invention.
  • FIG. 5 is a graph showing the size distribution of powder agglomerates obtained from lactose and resulting from the process of the present invention.
  • FIG. 6 is a graph showing the size distribution of powder agglomerates obtained from mometasone furoate and resulting from the process of the present invention.
  • FIG. 7 is a graph showing the size distribution of powder agglomerates obtained from a blend of montelukast and lactose and resulting from the process of the present invention.
  • a "patient” is a human or non-human mammal. In one embodiment, a patient is a human. In another embodiment, a patient is a non-human mammal.
  • the term "therapeutically effective amount” as used herein refers to an amount of the active pharmaceutical ingredient, or a composition thereof, that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from a disease or condition. .
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • dried particulate material refers to particles having a mean diameter of approximately 1-5 ⁇ , wherein the particles have a moisture content of less than 5% by weight.
  • binder agglomerate refers to a bound mass of small particulates.
  • the present invention involves, inter alia to a process where dried particulate material is rotated in an enclosed chamber arranged about a horizontal axis.
  • the process of the present invention allows preparation of greater quantities of powder agglomerates with minimal process development upon scaling up.
  • FIG. 2 depicts an apparatus (10) useful for conducting the process of the present invention.
  • FIG. 3 is an enlarged and cutaway view of the same apparatus where the chamber (1) rests on two cylinders (1 1).
  • a motor (12) also housed in the apparatus, is connected to the cylinders. Operation of the motor drives the cylinders in a circular pathway which in turn spins the chamber in the opposite direction about its horizontal axis (2).
  • FIG. 4 depicts a cutaway view of the chamber of one embodiment used in the process of the present invention.
  • the chamber (1) contains a powder bed (5) of the dried particulate material that rotates about a horizontal axis (2).
  • stress-strain vectors due to gravity and moment-induced shear surpass the cohesiveness of the granular material, causing a dislocation and subsequent cascade of particles down the incline of the powder bed.
  • the powder avalanche is a form of stress relaxation.
  • This cascade is restricted to a small region which is the sliding plane at the top of the powder bed (exposed surface).
  • the remander of the granular bed remains essentially motionless. This point of the powder bed is referred to as the "curl" (5a).
  • the dried particulate material to be agglomerated is first passed through a coarse sieve to loosen the material before being loaded in the chamber.
  • the dried particulate material can be passed through an ASTM-16 sieve or a sieve having similar pore sizes.
  • this sifting step is performed with gentle shaking which can be performed either mechanically or manually.
  • adding water to the particulate material such as by providing a humidifying environment, is not required.
  • the substantial absence of water in the process can result in a powder agglomerate which has a longer shelf-life than does powder agglomerate prepared with the addition of water to make the particulate material self- agglomerative.
  • the absence of water avoids physical, chemical, and microbial degradation processes which result from the presence of water in the final formulation (e.g., mold processes, hydrolysis, capillary binding).
  • the dried particulate material is agglomerated in the presence of less than 3% by weight, e.g., less than 1% by weight, of a binder.
  • the dried particulate material is loaded into the chamber having a horizontally disposed longitudinal axis.
  • the chamber is enclosed and can comprise a cylindrical shape or spherical shape.
  • the enclosed chamber can be an ovoid, having an egg shape.
  • the chamber can be fitted with a wire mesh, for example, a metallic wire mesh, to prevent wall effects, such as electrostatic attraction or particle-wall friction.
  • the operator can simply manually load the desired quantity of the dried particulate material.
  • conveyor or screw feeder systems introduce the material into the chamber.
  • the loading of the particulate powder fills about 20 to 75% of the volume of the chamber.
  • the particulate material fills no more than 60% of the chamber' s volume. In specific embodiments, the particulate material fills no more than 50% of the chamber' s volume.
  • At least 200 g of dried particulate material is loaded into the chamber, such as 200 g to 200 kg of dried particulate material. In certain embodiments, at least 500 g of dried particulate material is loaded into the chamber. In certain embodiments at least 10 kg of dried particulate material is loaded into the chamber.
  • the apparatus having the chamber includes a drive mechanism (e.g., a rotating shaft) for rotating the enclosed chamber about the horizontal axis for at least 300 revolutions, for example, for about 300 to about 60,000 revolutions.
  • the enclosed chamber is rotated for at least 600 revolutions.
  • the enclosed chamber is typically rotated about the horizontal axis at a speed of at least 5 rpm and no more than 150 rpm.
  • the enclosed chamber is rotated at from 10 to 120 rpm, and in other embodiments, at from 30 to 100 rpm.
  • Counting the number of powder avalanches provides another alternative for determining the duration of the process of the present invention.
  • the chamber is rotated until at least 600 powder avalanches occur before discharging the powdered agglomerate. In some embodiments, the chamber is rotated until at least 900 powder avalanches occur. If the chamber contains at least one glass wall, the powder avalanches can be counted manually or by using electronic sensing devices.
  • the powder agglomerate formed the process of the present invention can further include the step of agitating the discharged powder agglomerate from the chamber and on to a mesh screen to separate it from the residual particulate material (also referred as "fines").
  • the screen has an aperture width between 200 to 1000 microns.
  • the process of the present invention comprises transferring the discharged powder agglomerate into a container for storing or further processing a therapeutic agent.
  • the discharged powder agglomerate can be transferred into a dry powder inhaler reservoir, a tableting die, a capsule, a sachet, or a vial for injection.
  • Useful powder agglomerates produced by the process of the present invention include agglomerates ranging in size from between about 15 ⁇ to 3 mm, such as from 100 to about 1500 ⁇ . In some embodiments, the powder agglomerates have an average size of between about 300 and about 1,000 ⁇ .
  • the bulk densities of the powdered agglomerates resulting from the process of the present invention invention are from 0.1 to 0.5 g/mL, preferably a bulk density of 0.2 to 0.4 g/mL.
  • the powder agglomerates prepared by the present invention have a tight agglomerate size distribution.
  • no more than about 10% of the agglomerates are 50% smaller or 50% larger than the mean or target agglomerate size.
  • no more than about 10% of the agglomerates will be smaller than about 150 ⁇ or larger than about 450 ⁇ .
  • Dv stands for volume diameter of the agglomerates.
  • DvX is the volume diameter below which X percent of the log normal cumulative size distribution falls.
  • Dv90 is the volume diameter below which 90 percent of the log normal cumulative size distribution falls.
  • Dv50 is the volume diameter below which 50 percent of the log normal cumulative size distribution falls.
  • DvlO is the volume diameter below which 10 percent of the log normal cumulative size distribution falls.
  • Dv90 is defined to mean that at least about ninety percent of the powdered agglomerates have an agglomerate size of less than a certain agglomerate size.
  • Dv50 is defined to mean that at least 50% of the powdered agglomerates have an agglomerate size of less than a certain agglomerate size.
  • agglomerates useful in dry powder inhalers or other dosage forms, wherein the agglomerate includes at least one excipient and at least one active pharmaceutical ingredient that have a Dv90 less than about 1200 microns ( ⁇ ), or less than about 1000 microns ( ⁇ ).
  • agglomerates useful in dry powder inhalers or other dosage forms, wherein the agglomerate includes at least one pharmaceutically acceptable excipient and at least one active pharmaceutical ingredient that has Dv50 of less than about 5 microns ( ⁇ ) or less than about 3 microns ( ⁇ ).
  • Such agglomerate formulations are useful in dry powder inhaler systems, such as the TWISTHALER®, sold by Merck Sharp & Dohme Corp., Whitehouse, New Jersey, U.S.A.
  • the powdered agglomerates resulting from the process of the present invention expand the available administration options for various pharmaceutical active ingredients as well as pharmaceutically acceptable excipients which are used in mixtures therewith.
  • suitable drugs include those having poor bioavailability due to the drugs' limited water- solubility.
  • the drug- containing compositions are then formed into traditional oral dosage forms including tablets, capsules, and powder sachets.
  • the powdered agglomerates can be incorporated to form drug products where a smaller image size has a higher drug load, since the process results in agglomerates having a higher drug load due to the fact that agglomeration formed according to the process of the present invention require a lower concentration of excipients.
  • powdered agglomerates are prepared which include drugs that require delivery deep in the respiratory tract, preferably through powder inhalation such as inhaled corticosteroids, long acting beta agonists, long acting muscarinic agents, medium acting beta agonists, spleen tyrosine kinase inhibitors (Syk), and combinations thereof.
  • drugs that require delivery deep in the respiratory tract preferably through powder inhalation
  • Other agents which may require delivery in the respiratory tract include drugs for the treatment of pulmonary hypertension, central nervous system disorders, asthma, and chronic obstructive pulmonary disease.
  • the active pharmaceutical ingredients are selected from corticosteroids, dissociated steroids, ⁇ -agonists, anticholinergics, leukotriene antagonists, spleen tyrosine kinase (Syk) inhibitors, Janus kinase (JAK) inhibitors, Phosphodiesterase (PDE) Inhibitors, Soluble Guanylate Cyclase (sGC) modulators, serotonergic agents, antibiotics, and inhalable proteins or peptides.
  • the active pharmaceutical ingredients are selected from glycopyrrolate, ciclesonide, indacaterol, tiotropium, mometasone furoate, beclomethasone dipropionate, budesonide, fluticasone, dexamethasone, flunisolide, triamcinolone, salbutamol, albuterol, terbutaline, salmeterol, bitolterol, ipratropium bromide, oxitropium bromide, sodium cromoglycate, nedocromil sodium, montelukast, zafirlukast, pranlukast, formoterol, eformoterol, bambuterol, fenoterol, clenbuterol, procaterol, broxaterol, (22R)-6a,9 a -difluoro- ⁇ ⁇ , 21- dihydroxy-16a, 17 a-propylmethylenedioxy-4-pregnen-3,
  • the active pharmaceutical ingredients are selected from glycopyrrolate, ciclesonide, indacaterol, tiotropium, mometasone furoate, budesonide, fluticasone, triamcinolone, salmeterol, montelukast, zafirlukast, pranlukast, rizatriptan, tobramycin, and formoterol.
  • the active pharmaceutical ingredient is a corticosteroid, such as mometasone furoate.
  • Mometasone furoate is an antiinflammatory corticosteroid having the chemical name, 9,21-Dichloro-l 1( ⁇ ), 17-dihydroxy- 16(a)-methylpregna-l,4-diene-3,20-dione 17-(2 furoate). It is practically insoluble in water; slightly soluble in methanol, ethanol, and isopropanol; soluble in acetone and chloroform; and freely soluble in tetrahydrofuran. Its partition coefficient between octanol and water is greater than 5000. Mometasone can exist in various hydrated (e.g., as a monohydrate), crystalline and enantiomeric forms.
  • esters, salts, solvates such as hydrates, or solvates of such esters or salts, if any.
  • the term is also meant to cover both racemic mixtures as well as one or more optical isomers.
  • the drug in accordance with the present invention can also be an inhalable protein or a peptide such as insulin, interferons, calcitonins, parathyroid hormones, granulocyte colony-stimulating factor and the like.
  • Drug as used herein may refer to a single
  • pharmacologically active entity or to combinations of any two or more, an example of a useful combination being a dosage form including both a corticosteroid and a ⁇ -agonist.
  • the amount of drug administered will vary with a number of factors including, without limitation, the age, sex, weight, condition of the patient, the drug, the course of treatment, the number of doses per day and the like.
  • the amount of drug delivered per dose i.e., per inhalation, will generally range from about 10 ⁇ g to about 10,000 ⁇ g.
  • Doses of 25 ⁇ g, 50 ⁇ g, 75 ⁇ g, 100 ⁇ g, 125 ⁇ g, 150 ⁇ g, 175 ⁇ g, 200 ⁇ g, 250 ⁇ g, 300 ⁇ g, 400 ⁇ g and/or 500 ⁇ g are preferred.
  • the active pharmaceutical ingredient as well as pharmaceutically acceptable salts thereof may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition.
  • the invention further provides a pharmaceutical composition, which comprises an active pharmaceutical ingredient and a pharmaceutically acceptable excipient.
  • the excipients must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the dried particulate material to be agglomerated contains only the active pharmaceutical ingredient. In other embodiments of the process, the dried particulate material contains a blend of the active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients.
  • the dried particulate material contains only one or more pharmaceutically acceptable excipients.
  • the resulting powder agglomerate containing the one or more pharmaceutically acceptable excipients can be used in further processing steps for preparing useful pharmaceutical dosage forms.
  • the excipient used in the process is selected from polyhydroxy aldehydes, and polyhydroxy ketones.
  • Preferred polyhydroxy aldehydes and polyhydroxy ketones include hydrated and anhydrous saccharides selected from lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, mannitol, melezitose, starch, xylitol, mannitol, myoinositol, their derivatives, and the like.
  • the process is conducted with lactose.
  • the excipient is selected from sorbitol, xylitol, and mannitol.
  • the pharmaceutically acceptable excipient in accordance with the present invention is typically provided in, or reduced to, a particle size which is roughly congruent with the size of the particles of the active pharmaceutical ingredient as previously described.
  • agglomerates of mometasone furoate anhydrous USP will preferably be provided having particles of at least 80% ⁇ 5 ⁇ and at least 95% ⁇ 10 ⁇ (measured by volume distribution).
  • the excipient, such as anhydrous lactose, F will be provided having particles of at least 60% ⁇ 3 ⁇ , at least 80% under 5 ⁇ , and at least 95% ⁇ 10 ⁇ .
  • the average particle size is roughly the same for both and is less than 5 ⁇ .
  • a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g., containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device.
  • the container is rupturable or peel-openable on demand and the dose of e.g., the dry powder composition can be administered by inhalation via the device such as the DISKUS® device (GlaxoSmithKline).
  • the powdered agglomerates prepared by the process of the present invention are particularly useful for preparing powdered dosage form for dry powder inhalers, the agglomerates are also useful for preparing other dosage forms.
  • dosage forms for example may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, topical, inhaled, nasal, ocular, or parenteral (including intravenous and intramuscular) route.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the active pharmaceutical ingredient can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or
  • Sets 1 and 2 were simple one component systems, where Set 1 contained lactose only, and Set 2 contained mometasone furoate.
  • Set 3 contained a uniformly blended binary mixture of montelukast and lactose in 40:60 w/w ratio. The components of all three sets had a particle mean size of 2-5 ⁇ .
  • the components were passed through a 1.18 mm (ASTM-16M) sieve using gentle manual shaking.
  • ASTM-16M 1.18 mm
  • the drum was part of an apparatus which was a Revolution Powder Analyzer by Mercury Scientific, Model: Rev 2007.
  • the drum was then mounted on a rotating shaft and rotated about the horizontal axis at the defined speeds shown below in Table 1. After completion of the rotations, the powdered agglomerates were emptied on a 20M screen, and stored at ambient conditions prior to analysis. All runs were replicated three times.
  • a QICPIC particle analyzer (Symnpatec GmbH, Clausthal-Zellerfeld, Germany) which analyzes size and shape using dynamic image analysis. Briefly, this instrument captures images of dry particles in a fast moving air stream with a high speed digital camera. For analysis of the size distribution of the powdered agglomerates, the volume diameter below which 90, 50 and 10 percent of the log normal cumulative size distribution of the agglomerate fell were measured.
  • sphericity is defined as the ratio between the perimeter of a circle that has the same projected area as the particle to the measured perimeter, and is thus a value between 0 and 1.
  • the aspect ratio is defined as the ratio of the minimal and maximal Feret diameter, and is thus also between 0 and 1. Based on these definitions, both sphericity and aspect ratio of a sphere equal to 1. The sphericity distributions were determined at 90, 50, and 10 percent of the log normal cumulative sphericity distribution.
  • Table 2A provides the physical characteristics of powdered agglomerate prepared from lactose (LAC) as the single component (Set 1) with the values in parentheses indicating the standard deviation.
  • Figure 5 shows the size distribution of the Set 1 powdered agglomerates.
  • LAC-R1 389.52 589.38 804.55 0.36 0.65 0.87 0.95
  • LAC-R2 385.57 642.82 873.21 0.32 0.67 0.86 0.94
  • Table 2B provides the physical characteristics of powdered agglomerate prepared from mometasone furoate (MF) as the single component (Set 2) with the values in parentheses indicating the standard deviation.
  • Figure 6 shows the size distribution of the Set 2 powdered agglomerates.
  • Table 2C provides the physical characteristics of powdered agglomerate prepared from montelukast and lactose blend (MTL) (Set 3) with the values in parentheses indicating the standard deviation.
  • Figure 7 shows the size distribution of the Set 3 powdered agglomerates.
  • Tables 2A-2C demonstrate that the process of the present invention provides powdered agglomerates of both active pharmaceutical ingredients, excipients, and blends thereof with substantial uniformity. Standard deviations are within 10% of the mean values, where up to 15% is considered acceptable. Particle size distribution width, measured as the ratio of X90 to X10, is less than 4 which is typical of narrow to medium size distributions.

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Abstract

La présente invention concerne un procédé de préparation d'agglomérat de poudre à partir d'un appareil rotatif, comprenant : le chargement de matériau particulaire séché ayant un diamètre inférieur à 5 µm dans une chambre fermée agencée autour d'un axe horizontal ; la rotation de la chambre fermée autour de l'axe horizontal pendant au moins 300 tours pour former l'agglomérat de poudre ; et le déchargement de l'agglomérat de poudre depuis l'appareil. Les agglomérats de poudre sont utiles pour la préparation de formes pharmaceutiques courantes, en particulier une forme pharmaceutique en poudre séchée pour des inhalateurs de poudre sèche.
PCT/US2017/018246 2016-02-24 2017-02-17 Agglomération contrôlée de médicament ou mélanges médicament-excipient micronisés Ceased WO2017146994A1 (fr)

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Cited By (1)

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CN115381799A (zh) * 2022-09-26 2022-11-25 苏州易合医药有限公司 一种涡旋混合制备阿莫西林吸入用球状颗粒的方法

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US2561055A (en) * 1943-07-19 1951-07-17 Monsanto Chemicals Method of making pellets
US4161516A (en) * 1975-07-25 1979-07-17 Fisons Limited Composition for treating airway disease
US5551489A (en) * 1993-10-01 1996-09-03 Astra Aktiebolag Agglomeration of finely divided powders
US20030003229A1 (en) * 2001-06-13 2003-01-02 Walton Otis R. Centrifuged rotating drum for treating cohesive powders
US20040198708A1 (en) * 2000-08-04 2004-10-07 Kaplan Leonard W. Formulations of mometasone and a bronchodilator for pulmonary administration
US20050019411A1 (en) * 2001-10-18 2005-01-27 Paolo Colombo Powder for nasal administration of drugs
US20060159803A1 (en) * 2004-12-30 2006-07-20 Gottemoller Thomas V Polyol coated particles
US20100233276A1 (en) * 2007-10-26 2010-09-16 Universita' Degli Studi Di Parma Compositions in powder form made of soft agglomerates of a micronized drug and of a two-components excipient, and process for their preparation
US20110026760A1 (en) * 2009-07-29 2011-02-03 Mercury Scientifc Inc. Method for characterizing powder in a rotating cylindrical container by image analysis

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2561055A (en) * 1943-07-19 1951-07-17 Monsanto Chemicals Method of making pellets
US4161516A (en) * 1975-07-25 1979-07-17 Fisons Limited Composition for treating airway disease
US5551489A (en) * 1993-10-01 1996-09-03 Astra Aktiebolag Agglomeration of finely divided powders
US20040198708A1 (en) * 2000-08-04 2004-10-07 Kaplan Leonard W. Formulations of mometasone and a bronchodilator for pulmonary administration
US20030003229A1 (en) * 2001-06-13 2003-01-02 Walton Otis R. Centrifuged rotating drum for treating cohesive powders
US20050019411A1 (en) * 2001-10-18 2005-01-27 Paolo Colombo Powder for nasal administration of drugs
US20060159803A1 (en) * 2004-12-30 2006-07-20 Gottemoller Thomas V Polyol coated particles
US20100233276A1 (en) * 2007-10-26 2010-09-16 Universita' Degli Studi Di Parma Compositions in powder form made of soft agglomerates of a micronized drug and of a two-components excipient, and process for their preparation
US20110026760A1 (en) * 2009-07-29 2011-02-03 Mercury Scientifc Inc. Method for characterizing powder in a rotating cylindrical container by image analysis

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115381799A (zh) * 2022-09-26 2022-11-25 苏州易合医药有限公司 一种涡旋混合制备阿莫西林吸入用球状颗粒的方法
CN115381799B (zh) * 2022-09-26 2023-11-03 苏州易合医药有限公司 一种涡旋混合制备阿莫西林吸入用球状颗粒的方法

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